PROJECT SUMMARY The elucidation of new, highly stereocontrolled reactions for the construction of carbon–nitrogen and carbon-carbon bonds remains a central goal of chemical synthesis. Over the years, various discoveries in this area have enabled the efficient preparation of a wide variety of important medicinals that have benefited humanity. This grant application requests support for the Principal Investigator's new projects in the area of organozinc(II)-promoted heterocycle synthesis. The present application emphasizes the discovery and synthetic application of a new and potentially powerful intramolecular C- N/C-Zn bond forming cascade involving the addition of functionalized zinc amides, derived from N,N- dimethylhydrazines, to allenes, dienes, enynes, vinylcyclopropanes and vinylcyclobutanes. We believe this method will receive considerable utilization as a vehicle for the stereocontrolled synthesis of biologically relevant small molecules. The application of the new chemistry discovered during the proposed grant period should be readily applicable to the synthesis of numerous stereochemically rich heterocycles of pharmacological significance. The research program described in this grant application is expected to provide valuable insight into new reaction types that should serve to elucidate specific factors that are critical to the development of consecutive intramolecular C-N/C-Zn (and thus: C-N/C-Electrophile) bond formation in the context of stereocontrolled small molecule synthesis.

PROJECT NARRATIVE The research program described in this grant application is expected to provide new insights into the organozinc-mediated metalloamination/cyclization-electrophilic functionalization of structurally diverse N,N-dimethylhydrazinoalkenes, allenes, dienes, enynes, vinylcyclopropanes and vinylcyclobutanes. In addition, a prospective means for achieving a catalytic asymmetric version of metalloamination/cyclization will be explored as well as new methods for the electrophilic functionalization of the resultant metallacycles. This new synthetic method is expected to provide concise approaches to numerous stereochemically rich heterocycles of pharmacological significance.